Peroxisome which is an intracellular granule is a small granule in the cytoplasm containing catalase and a group of oxidases. Peroxisome proliferators which proliferate peroxisome are thought as important controlling elements of lipid metabolism in the body. A nuclear receptor, PPAR, which is activated by the peroxisome proliferator has turned out to be a multifunctional receptor concerning incretion, metabolism, inflammation or the like. Therefore, the ligand is thought to be able to apply as various medicines and the number of researches is recently increasing.
The subtype genes of PPARs are found from various animal organs and formed a family. In mammals, PPARs are classified into three subtypes of PPARα, PPARδ (also referred to as PPARγ and PPARγ.
The drugs of the fibrate group used as an antihyperlipemic drug are thought to show the activity by PPARα activation-mediated transcriptional enhancement of the gene group which improves serum lipid. Additionally, it is suggested that PPARα may relate to bone metabolism and expression of the activity of non-steroidal anti-inflammatory drugs.
The thiazolidindion compounds, which are improving drugs for insulin resistance, are ligands of PPARγ. As these compounds show hypoglycemic action, hypolipidemic action, adipocyte differentiation-inducing action or the like, PPARγ agonists are expected to develop as therapeutic agents for diabetes, hyperlipidemia, obesity or the like. Furthermore, PPARγ agonists are expected to be therapeutic agents for chronic pancreatitis, inflammatory colitis, glomerulosclerosis, Alzheimer's disease, psoriasis, parkinsonism, Basedow's disease, chronic rheumatoid arthritis, cancer (breast cancer, colonic cancer, prostatic cancer or the like), sterility or the like.
It was reported that transgenic mice in which PPARδ is overexpressed specifically in adipocyte were difficult to get fat or the like. Therefore, PPARδ agonists can be used as an antiobesity or antidiabetic drug. Additionally, PPARδ agonists are suggested the possibility as therapeutic agents for colonic cancer, osteoporosis, sterility, psoriasis, multiple sclerosis or the like.
Based on these findings, PPAR agonists are expected to be useful for treatment or prevention of hyperlipidemia, diabetes, hyperglycosemia, insulin resistance, obesity, arteriosclerosis, atherosclerosis, hypertension, syndrome X, inflammation, allergic disease (inflammatory colitis, chronic rheumatoid arthritis, chronic pancreatitis, multiple sclerosis, glomerulosclerosis, psoriasis or the like), osteoporosis, sterility, cancer, Alzheimer's disease, parkinsonism, Basedow's disease or the like (Non-Patent Document 1).
Patent Document 1 disclosed benzothiazole derivatives containing piperazine which can be used as antiobesity drugs or the like. However, it did not disclose the PPAR agonistic activity at all.
Patent Document 2 disclosed benzothiazole or benzoxazole derivatives containing piperazine or piperidine as antiviral drugs. However, it did not disclose the PPAR agonistic activity at all.
Patent Document 3 disclosed benzoxazole derivatives containing pyrrolidine as PPARγ agonists. However, it did not disclose a compound containing piperazine or piperidine.
Patent Document 4 and 5 disclosed that compounds containing piperazine have antiallergic action or the like. Non-patent Document 2 disclosed compounds containing piperazine as glycoprotein IIb/IIIa antagonists. Patent Document 6 disclosed compounds containing piperazine as CB1 antagonists. However, they did not disclose the PPAR agonistic activity at all.
Patent Document 7 and 8 disclosed compounds containing piperazine or piperidine as PPAR modulators. However, these compounds are characterized by having a sulfonyl group between piperazine and a phenyl group as a linker.    [Patent Document 1] WO 00/006558    [Patent Document 2] EP 398425    [Patent Document 3] WO 97/31907    [Patent Document 4] JP1992-345765    [Patent Document 5] JP1997-208570    [Patent Document 6] WO 2006/060461    [Patent Document 7] WO 2004/092117    [Patent Document 8] WO 2005/115983    [Non-patent Document 1]Current Medicinal Chemistry, 2003, Vol. 10, p.p. 267-280    [Non-patent Document 2]Bioorganic & Medical Chemistry Letters, 1998, Vol. 8, p.p. 1531-1536